Accuracy of Side-Chain Prediction Upon Near-Native Protein Backbones Generated by Ab Initio Folding Methods

ABSTRACT The ab initio folding problem can be divided into two sequential tasks of approximately equal computational complex-ity: the generation of native-like backbone folds and the positioning of side chains upon these backbones. The prediction of side-chain confor-mation in this context is challenging, because at best only the near-native global fold of the protein is known. To test the effect of displace-ments in the protein backbones on side-chain prediction for folds generated ab initio, sets of near-native backbones (I 4 A ̊ Ca RMS error) for four small proteins were generated by two methods. The steric environment surrounding each residue was probed by placing the side chains in the native conformation on each of these decoys, followed by torsion-space optimi-zation to remove steric clashes on a rigid back-bone. We observe that on average 40 % of the x1 angles were displaced by 40 ° or more, effec-tively setting the limits in accuracy for side-chain modeling under these conditions. Three different algorithms were subsequently used for prediction of side-chain conformation. The average prediction accuracy for the three meth-ods was remarkably similar: 49 % to 51 % of the x1 angles were predicted correctly overall (33% to 36 % of the x112 angles). Interestingly, when the inter-side-chain interactions were disre-garded, the mean accuracy increased.Aconsen-sus approach is described, in which side-chain conformations are defined based on the most frequently predicted x angles for a given method upon each set of near-native back-bones. We find that consensus modeling, which de facto includes backbone flexibility, im-proves side-chain prediction: x1 accuracy im-proved to 51–54 % (36–42 % of x112). Implica-tions of a consensus method for ab initio protein structure prediction are discussed. Pro